Utility of pharmacogenomic testing in predicting intolerance to BTK inhibitors.

7541 Background: Oral inhibitors of Bruton’s tyrosine kinase (BTKi) are used for a number of B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL) and lymphoplasmacytic lymphoma (LPL). Real-world data has demonstrated that BTKi discontinuation is commonly due to intolerance, but contributing factors are not fully understood. Prior work suggests that cytochrome P450 (CYP) polymorphisms may increase the risk of targeted therapy discontinuation in CLL. We utilized pharmacogenomic (PGx) testing in Veterans treated with BTKi to evaluate the potential contribution of CYP polymorphisms to intolerance and responses to BTKi. Methods: We identified Veterans receiving care through the Veterans Administration (VA) who were prescribed a BTKi and underwent testing through the Pharmacogenomic Testing for Veterans (PHASER) program, currently offered at 22 VA facilities. We analyzed factors including time on BTKi therapy, reasons for discontinuation, and use of concomitant medications known to strongly inhibit CYP. Event-free survival (EFS) was defined as time from BTKi initiation to discontinuation. Results: Eighty-nine Veterans treated with BTKi who had PGx testing were identified, of which 97% (86) were male and 85% (76) were diagnosed with CLL. Other diagnoses included LPL (4), MCL (3), and MZL (3). Seventy-seven patients (pts) were treated with ibrutinib, nine with acalabrutinib and three with zanubrutinib. Three pts had poor metabolizer genotype (PMG) for CYP2C19 and 25 pts received strong CYP2C19 inhibitors (inh). Thirty-two pts had PMG for CYP2D6, and 12 pts received strong CYP2D6 inh. With a median follow up time of 38.9 months, 25 pts (28%) permanently discontinued due to intolerance and 10 pts (11%) progressed on BTKi therapy. Another 25 pts temporarily discontinued therapy. Median duration of BTKi therapy was 11.0 months for pts discontinuing for intolerance, 23.2 months for pts discontinuing for progression, and 38.5 months for pts not discontinuing therapy. Reasons for intolerance included arrhythmia, bleeding, and infections. EFS due to intolerance or progression was not statistically different between pts who were either CYP2C19 PMG or who received strong CYP2C19 inh, compared to all other pts. Interestingly, EFS due to intolerance alone was statistically different comparing these groups (p = 0.014, median 49.4m vs NR), but EFS due to progression was not (p = 0.76, median 79.6m vs NR). EFS was not significantly different comparing pts who were either receiving strong CYP2D6 inh or were PM to those who were not. Conclusions: We found that Veterans who were treated with BTKi and who either took concomitant strong CYP2C19 inh or had a CYP2C19 PMG were more likely to have intolerable side effects of BTKi therapy leading to discontinuation. Our results suggest that evaluating polypharmacy and PGx factors should be considered when prescribing BTKi.

Duke Scholars

Author Fahmin Basher